Perspective Chapter: Appraisal of Paclitaxel (Taxol) Pros and Cons in the Management of Cancer – Prospects in Drug Repurposing

Abstract

Paclitaxel (Taxol) is potent natural anticancer drug that has evolved over the years. It has been useful in the management of many cancers. Hence, this review aims to appraise the pros and cons of paclitaxel in the management of cancers using literature. Paclitaxel acts by obstructing mitotic spindle formation attributed to clampdown of mitotic clampdown hence arresting the cell cycle at the G2/M phase. Some of the notable side effects of paclitaxel usage include: hair loss, numbness, bone marrow suppression, muscle pain, allergic reactions, diarrhea, etc. Among the mechanism of paclitaxel resistance are P-glycoprotein efflux pumps, mutation in tubulin and alterations in binding regions of β-tubulin, altered function of cytokine expression as well as apoptotic Bcl-2 and p53. Combination of paclitaxel with cisplatin clearly improves the duration of progression-free survival and of overall survival of breast cancer. Paclitaxel which is a valuable natural anticancer drug seems promising in the management of non-cancer diseases such as COVID-19, renal and hepatic fibrosis, inflammation, skin disorders, axon regeneration, limb salvage, and coronary artery restenosis. With the advancement of technology, it is expected that the biosynthesis, chemo-resistance as well as its targeted delivery would unfold and perhaps open new uses and vista to the old drug of about five decades ago.

1. Introduction

One of the World Health Organization (WHO) list of essential medicine is paclitaxel which is also known as Taxol and belongs to the taxane family (Figure 1). It’s an approved drug used to treat some cancers which include: breast, ovarian, lung, esophageal, cervical among other, it has a total market value of over $1 billion per year [1, 2]. Some of the notable side effects of paclitaxel usage include: hair loss, numbness, bone marrow suppression, muscle pain, allergic reactions, diarrhea, etc. [3].

Figure 1.

Structure of paclitaxel.

One of the remarkable natural anticancer drugs—paclitaxel was first extracted from the Pacific yew tree, Taxus brevifolia in 1971. The yield from the bark of the yew tree was 0.01–0.05% which was low and this prompted the search for alternative means of synthesis which range from microbial fermentation, chemical synthesis, tissue, and cell culture [4]. It acts by obstructing mitotic spindle formation attributed to clampdown of mitotic clampdown hence arresting the cell cycle at the G₂/M phase [5].

Among the mechanism of paclitaxel resistance are P-glycoprotein efflux pumps, mutation in tubulin and alterations in binding regions of β-tubulin, altered function of cytokine expression as well as well as apoptotic Bcl-2 and p53 [6]. Combination of paclitaxel with cisplatin clearly improves the duration of progression-free survival and of overall survival of breast cancer [7].

Earlier development shows that the combination of nab-paclitaxel and gemcitabine significantly improved the survival of patients with metastatic pancreatic cancer [8]. Recently, low-dose paclitaxel seems promising in treating non-cancer diseases, such as skin disorders, renal and hepatic fibrosis, inflammation, axon regeneration, limb salvage, and coronary artery restenosis. Future studies would help to understand the mechanisms underlying these effects in order to design therapies with specificity [9].

Nanocarrier systems including nanoparticles, liposomes, micelles, bioconjugates, and dendrimers have been employed in order to improve paclitaxel solubility and eliminate undesired side effects [10].

In the review, we examined the history, synthesis and biosynthesis of paclitaxel and also highlight the usage in the treatment of various cancers. We also presented the mechanism of action, combination with other drugs and well as the side effects and mechanisms of resistance. Hence, we concluded and provided future directions on paclitaxel with increasing evidence in the management of other disease other than cancer.

2. Materials and methods

2.1 Literature search

Literature search was done across many databases such as Google Scholar, PubMed, Embase, and Scopus using the keywords “Paclitaxel” and “Cancer.” A lot of research article was obtained as this area has been explored for the past 50 years. Preprints that have not been peer-reviewed; non-cancer studies were excluded as well as gray literature. This was filtered with abstract, title and full text to identify relevant articles that can be integrated to assess the appraisal of paclitaxel (Taxol) in the management of cancers. The other articles were excluded by abstract, title or full text after the authors have read the abstract or articles and discovered the articles do not adhere to the objectives of our review.

3. History and synthesis

Paclitaxel has been previously extracted from the bark of the Pacific Northwest yew tree which is one of eight varieties of Taxus species specifically the Taxus brevifolia [1, 11]. The yew tree has been historically used in the production spear points and other weapons, household implements and diverse tools [12, 13]. The active compound in paclitaxel was identified by Mansukh Wani and Monroe Wall in 1971 [14, 15, 16]. The drug was also selected that same year by the NCI as a candidate for preclinical development and took the crucial step of entering into an agreement with the National Forest Service to ensure a harvest of the yew [17, 18]. A breakthrough in the development of paclitaxel occurred in 1979 when Dr. Susan Horwitz at Albert Einstein Medical College in New York identified the drug’s unique mechanism of action as a promoter of microtubule assembly and its cytostatic activity on many types of tumors, thus increasing scientific interest in studying the drug [19, 20]. According to the National Cancer Institute (NCI), the Taxus brevifolia has a very poor Taxol content of only about 0.06% in the bark making it incapable of meeting the market and research’s needs [21, 22]. It was then concluded that the slow growth rate and high cost of production of paclitaxel made production impractical, non-environmentally conscious and financially burdening resulting in its insufficiency as a natural source of paclitaxel [23, 24]. The isolation of Taxol from endophytic fungus was also used to produce Taxol [11, 25]. This is done by the chemical conversion of 10-deacetylbaccatin-III to Taxol using synthetic and semi-synthetic methods [25]. Fermentation is also used to produce paclitaxel from microorganisms but it produces a small yield of between 24 ng and 70 μg per liter and it is very unstable [26].

3.1 Biosynthesis

Paclitaxel can be synthesized from the isoprenoid precursors, including IPP (isopentenyl pyrophosphate) and its isomer DMAPP (dimethylallyl pyrophosphate) utilized by organisms in the biosynthesis of terpenes and terpenoids, which can be produced through the MVA (mevalonate) pathway and the MEP (methylerythritol phosphate) pathway [4] as shown in Figure 2.

Figure 2.

Biosynthetic pathway of paclitaxel [4].

3.2 Mechanism of action

Paclitaxel is a chemotherapeutic drug functioning as a mitotic inhibitor that is used to treat common cancers [21, 25]. Paclitaxel is known to be the earliest microtubule-stabilizing agent that is able to arrest the cell cycle in the G₂/M phase and also promote apoptotic cell death [27, 28]. In preclinical in vitro studies, Taxol with concentrations as low as 0.05 μmol/L have been shown to promote microtubule assembly by decreasing the lag time for the microtubule assembly, and also to shift its equilibrium in favor of microtubule formation [29, 30]. It performs this role by interrupting the normal function of microtubule growth by hyper-stabilizing the structure, preventing the dissociation of microtubules, blocking cell cycle progression, preventing mitosis, and inhibiting the growth of cancer cells [31, 32]. In essence, Taxol reduces the concentration of tubulin that is needed for the assembly of microtubule in the presence or absence of factors that are usually essential for this function, such as exogenous GTP or microtubule-associated proteins [33]. Microtubules treated with Taxol are known to be stable even after a short period of treatment with calcium or low temperatures, conditions that easily promote disassembly [27]. This unusual stability results in the inhibition of the normal dynamic reorganization of the microtubule network [34]. Specifically, paclitaxel binds to the Taxol-binding domain of the β subunit of tubulin which is the “building block” of microtubules, and the binding of paclitaxel locks these building blocks in place preventing their depolymerization [35]. The complex compound formed (microtubule/paclitaxel) is unable to disassemble, thus reducing the critical concentration of the assembled tubulin subunits and increases the percentage of assembled tubulin subunits (shortening and lengthening) blocking the progression to mitosis [2]. As an anticancer drug, the microtubules in the prophase stage forms a spindle that pulls the chromosomes away from the equator to the poles [36]. During later stages, they depolymerize and the spindle structure dissolves [29] and the exposure to cold temperatures and calcium ions can also trigger depolymerization of microtubules [37]. The binding site of paclitaxel has been shown to be different from that for guanosine triphosphate, vinca alkaloids, colchicine, or podophyllotoxin and is present on the microtubule rather than tubulin dimers [38]. The mechanism of action of paclitaxel has been proposed on the basis of its effective action as a chemotherapeutic drug for different types of cancers.

3.3 Repurposing of paclitaxel for possible therapeutic outcomes

Drug repurposing has become an economical as it saves money and time, it also overcomes development risk associated with new drugs. Great benefits that exist with drug repurposing has already been outlined especially the knowledge of the mechanism of actions of the drugs that has been studied using new methods such as genomic expression and in vitro drug screening and target verification. Paclitaxel has been studied to show its effects in different types of cancers. Currently, new studies have also shown its involvement in non-cancer diseases also such as fibrosis. Zhang et al. [9] indicated that signal transducer and activator of transcription 3 (STAT3) were reduced in mice and in vitro in a dose dependent manner. They hypothesized that the administration of low doses of paclitaxel administration, may block the STAT3 (signal transducer and activator of transcription 3). This singular activity is responsible the attenuation of fibrous that has unilateral ureteral obstruction.

3.4 Appraisal of treatment effects/success

Rowinsky and collaborators [25] reported an excellent review on the preclinical and early clinical trials with paclitaxel and observed that 30% of the patients with ovarian achieved a complete remission [39]. Shortly after the original report of activity in ovarian cancer, three additional clinical trials provided confirmation that responses are observed (mostly partial remissions) in 20–50% of the patients with this disease.

Sparano et al. [40] experimentally depicted that paclitaxel significantly improves overall survival. There was also a 32% reduction in the hazard ratio for death afforded by weekly paclitaxel which was observed in a similar administration of anthracycline-containing chemotherapy. Sparano et al. [40] results are in consonant with studies of metastatic breast cancer that demonstrated a beneficial administration of paclitaxel weekly. Zhu et al. [41] explained in his journal that paclitaxel in combination with immunotherapy can increase the efficacy of treatment against breast cancer by inhibiting the normal function of Tregs and thus reversing the immune escape of tumors.

O’Shaughnessy et al. [42] performed a randomized clinical trial including 139 patients and suggested that paclitaxel in combination with alisertib improves progression-free survival observed in patients with ER-positive, ERBB2-negative or triple-negative metastatic breast cancer which had been pretreated with endocrine therapy. Markman et al. [43] evaluated the activity of single agent weekly paclitaxel in patients with both platinum and paclitaxel (delivered every 3 weeks)—resistant ovarian cancer. Forty-eight patients with platinum and paclitaxel-resistant ovarian cancer received single agent weekly paclitaxel (80 mg/m²/week). It was observed that the weekly administration of paclitaxel can be a useful management approach in women with both platinum and paclitaxel (given every 3 weeks)-resistant ovarian cancer.

4. Combinations with other drugs

Studies have shown that combination chemotherapy produces faster response rates and longer progression-free survival than single agents [39, 44, 45]. They remain the mainstay of therapy for patients with advanced breast cancer, and these regimens often include the anthracycline doxorubicin. When paclitaxel and MG1 were combined experimentally, their combination improved the efficacy of all of the breast cancer models tested, demonstrates greater efficiency in murine tumor models, greater tumor killing in vivo and thus is a promising alternative approach for the treatment of patients with refractory breast cancer [39]. Kawiak et al. [46] experimental study indicated that plumbagin increases the sensitivity of breast cancer cells to paclitaxel. The role of ERK (a component of mitogen-activated protein kinases that controls cell proliferation and survival) in plumbagin-mediated sensitization of breast cancer cells to paclitaxel was shown through the enhancement of the synergistic effect between compounds in cells with decreased ERK expression. These results imply that plumbagin can inhibit the activation of ERK in breast cancer cells and this plays a vital role in the sensitization of cells to paclitaxel-induced cell death [46].

Elserafi et al. demonstrated experimentally that the combination chemotherapy of paclitaxel and cisplatin provided similar response rate, lower toxic effect and overall survival when compared sequentially and in combination [44]. Also, Steuer et al. [45] showed that the combination of carboplatin-paclitaxel had a more favorable toxic-effect profile when compared to the combination of cisplatin-etoposide [45]. An experiment was carried out by Shroff et al. to evaluate the association between progression-free survival and the addition of nanoparticle albumin-bound (nab)-paclitaxel to gemcitabine-cisplatin for the treatment of patients with advanced biliary tract cancer. The result indicated that the treatment with nab-paclitaxel in addition to gemcitabine-cisplatin prolonged median progression-free survival, response rate and overall survival when compared to controls treated with gemcitabine-cisplatin alone [47, 48].

A combination of chemotherapeutic drugs doxorubicin and paclitaxel are known to be active in the treatment of advanced breast cancer. However, earlier studies indicated that this combination had a high incidence of congestive heart failure which was caused by increased exposure to doxorubicin and its metabolite doxorubicinol [49, 50]. Limitations of the paclitaxel-doxorubicin-cisplatin (TAP) regimen in the treatment of endometrial cancer include tolerability and cumbersome scheduling [51, 52]. In a phase 3 study of the efficacy and safety of the albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine versus gemcitabine monotherapy in patients with metastatic pancreatic cancer, the combination drug significantly improved overall survival, progression-free survival, and response rate [53, 54]. Combination therapy resulted both in a superior overall response rate and a superior time to treatment failure, two frequent measures of efficacy in metastatic chemotherapy trials [55].

5. Side effects/toxicity in organs

Traditional paclitaxel has a very poor solubility in water, and their solvents are likely to cause serious adverse effects [56]. There is evidence in the literature to suggest that paclitaxel effects are concentration-dependent. Adverse effects associated with paclitaxel administration include the peripheral neuropathy, hypersensitive reactions, myelosuppression, hepatotoxicity, bradycardia, cardiotoxicity, myalgias, hypotension, diarrhea, arthralgias, nausea, mucositis, gastrointestinal toxicity, and alopecia [57].

5.1 Myelosuppression

A major dose-limiting side effect of the administration of paclitaxel is myelosuppression which is known as bone marrow suppression that results in the decrease in the production of blood cells [57]. Specifically, paclitaxel administration results in grade IV leukopenia and neutropenia in about 26 and 68% of patients, respectively [58].

5.2 Hypersensitivity reactions

Hypersensitive reactions are mostly encountered either during or shortly after infusion with paclitaxel and the onset is usually very rapid, and seen within a few minutes of starting the infusion [59, 60]. Studies have shown that the solvent for paclitaxel (Cremophor EL®, castor oil vehicle) plays a very crucial role in hypersensitivity reactions such as anaphylactoid hypersensitivity reactions, abnormal lipoprotein patterns, hyperlipidemia, aggregation of erythrocytes and peripheral neuropathy which has been mediated by kinetic interference [61, 62, 63].

5.3 Neuropathy

Paclitaxel is known to cause weakness, cold sensitivity, numbness, pain from muscle and nerve damage to the hands and feet. Higher doses of paclitaxel are associated with an increased incidence of neuropathy, in fact, grade 3 or 4 neutropenia was observed in 68% [64, 65]. The effect of paclitaxel on microtubule assembly and disassembly reduces the normal axonal transport system leading to a length-dependent sensorimotor axonal neuropathy [66].

5.4 Renal and hepatic toxicities

Renal as well as hepatic toxicities are also a clinical concern in the administration of paclitaxel because they may compromise essential organ functions, impair renal excretion and reduce metabolism which lead to increased risk of other severe adverse effects [67]. This toxicity may be related to germline variations, such as single-nucleotide polymorphisms (SNPs) in genes that affect the pharmacokinetics and/or pharmacodynamics of paclitaxel [68].

5.5 Myalgias and arthralgias

Paclitaxel causes a syndrome characterized by diffuse myalgias and arthralgias, which can be resistant to opioids and other pain medications. Patients have reported pain that typically starts between day 2 and day 7 of administration and peaks on days 3–4 but remains consistent in intensity and duration with continuation of drug administration [58].

5.6 Dermatological adverse effects

Photosensitivity, pustular eruptions, folliculitis, extravasation, dorsal hand-foot syndrome, hair and nail changes, fixed erythrodysesthesia and also pigmentary changes are all caused by prolonged administration of paclitaxel [61].

6. Resistance

Drug resistance still remains the fundamental limiting factor to achieving cures to patients with cancer. Paclitaxel has been established as the first-line chemotherapeutic treatment drug for breast cancer [69, 70]. Mechanisms of drug resistance include over-expression of P-glycoprotein efflux pump, alterations in binding regions of β-tubulin and tubulin mutations, reduced function of significant apoptosis proteins (such as Bcl-2 and p53), alterations in cytokine expression (such as Interleukin-6), paclitaxel detoxification mediated by CYP [6], altered expression of regulatory proteins. These proteins include keratin 17 (KRT17) in cervical cancer cells, which may increase cell migration and PTX survival, or fibronectin type III domain-containing protein 5 (FNDC5), which could promote paclitaxel sensitivity by inhibiting NF-κB/MDR1 signaling in NSCLC [71], as well as microtubule specific effects with mutated β-tubulin, varied levels of β-tubulin isotypes, and chemical modification of tubulin [72]. Experimentally using indirect immunofluorescence and electron microscopy, acquired Taxol resistance in Chinese hamster ovary cell lines possessed altered α-tubulin or β-tubulin and required Taxol in the medium for normal growth have demonstrated that these resistant cells have mutations in tubulin, resulting in impaired microtubule assembly. In essence, continuous exposure to Taxol is required for polymerization to proceed normally, thereby promoting the formation of functional microtubules.

The ABC transporters are well known to be energy dependent transporters that exist across the cell membrane and transfer substrate across the cells using hydrolysis of ATP [32, 72]. Increased expression of ABC transporters such as ABCB1, ABCB4, and ABCG2 mRNA resulted in efflux of anticancer drug paclitaxel (pumping drug out the cell), leading to reduction in their efficacy and development of multidrug resistance (MDR) cells [73]. ABCB1 belongs to ABC transporter family and encodes a membrane protein P-glycoprotein, which is a well-known efflux pump responsible for Multi drug resistance [74]. Cells resistant to paclitaxel showed cross-resistance to other hydrophobic drugs and exhibited increased level of P-glycoprotein [64].

7. Conclusion and future direction

Plant-based medicines has shown potent anti-cancer, anti-diabetic, anti-viral and neuroprotective effect [75, 76, 77]. Notable pros of paclitaxel’s have been its usage in many cancers, high success rate from preclinical and clinical trial data, its combinatorial properties with other drugs. Also, it has also been shown to be promising in treating non-cancer diseases such as renal and hepatic fibrosis, inflammation, skin disorders, axon regeneration, limb salvage, and coronary artery restenosis [9]. Further research would be needful to show insight to the mechanistic mode of action in various diseases processes. It was recently reported by [78] that through protein-protein network analysis (bioinformatic and proteomics data analysis). Paclitaxel was the most potent candidate showcasing anti-cancer as well as anti-viral property. More wet lab research is needed to validate and enhance its repurposing strategy.

Also, notable cons about paclitaxel that would be improved in the incoming years include: utilization of biotechnology to improve biosynthesis of paclitaxel will unfold with improved technologies and technological application. Overcoming the chemo-resistance associated with paclitaxel would enhance its usage in many other diseases as well as novel combination with other drugs/therapies will uncover faster response and survival in patients. Modification with targeted deliveries like novel liposomes and magnetic particle preparations would ensure prompt pharmacological action. Alternating the formulation approach to minimize its toxicity as a result of Cremophor. This assessment of the pros and cons of paclitaxel is discussed in this chapter (Figure 3 below).

Figure 3.

Overview of the pros and cons of paclitaxel in cancer management.

Researchers envisages more development and improvement in the near future for synthesis, overcoming chemo-resistance, combination with other drugs and repurposing and application in non-cancer diseases of the compound extracted from the bark of pacific yew tree some five decades ago.

Conflict of interest

The authors declare no conflict of interest.